Process for the production of z-cyclo-
alkylamino derivatives of i,x-benzo-
diazepines



United States Patent Office 3,189,603 Patented June 15, 1965 This application is a divisional application of my copending application, Serial No. 204,301 filed April 9, 1962,

now US. Patent 3,138,586.

This invention relates to l,4 benzodiazepines. More particularly, this invention relates to a novel process for the production of 2-cycloalkylamino derivatives of 1,4- benzodiazepines having the formula:

useful for this reaction is described and claimed in copend ing application Serial No. 305,503. I

wherein R represents hydrogen; R represents a cycloparafiin group such as cyclopropyl, cyclopropylmethyl, cyclobutyl or cyclopentyl and R and R each represents hydrogen, halogen such as chlorine and bromine, lower alkyl such as methyl, ethyl or propyl and lower alkoxy such as methoxy or ethoxy. The symbols R R R and R as used hereinafter have the same meaning as defined.

The above compounds are important thereapeutic agents. They are useful, for example, as tranquilizers. In addition, they are important intermediates for the production of other 1,4-benzodiazepines.

In accordance with my invention the above compounds are synthesized by reacting an intermediate compound represented by the following structural formula:

wherein R represents a lower alkyl group such as methyl, ethyl or propyl or an aryl group such as phenyl or tolyl with an excess of cycloalkyl or cycloalkylalkylamine of the formula R NH Suitable amines useful for this reaction are, for ex- 3 ample, cyclopropylamine, cyclopropylmethylamine, cyclo-' butylamine and cyclopentylamine.

The reaction is generally eifected at a temperature range of 5 to 0 C. over a period of about 12 to 18 hours. The precipitated reaction product may be recovered from the reaction medium by conventional means such as by filtration or centifugation. The starting intermediate The foregoing reaction may be conveniently expressed in the following equation:

The following examples are included in order further to illustrate the invention.

Example 1 To a solution of 4.70 g. of cyclopropylamine in 3.62 ml. of methanol is added 2.00 g. of 2-mesyloxymethyl-4- phenyl-'6-chloroquinazoline-3-oxide and the mixture is maintained at 5 to 0 C. for 16-18 hours. A White crystalline precipitate of 7-ch1oro-2-cyclopropylamino-5- phenyl-3H-1,4-benzodiazepine-4-oxide is formed which melts at 222-232 C. The compound is filtered oil and recrystallized from methanol, the recrystallized product melting at 248 251 C.

Example 2 To a solution of 17.6 g. of cyclopropylmethylamine in 13.4 ml. of methanol is added 6.0 g. of 2-mesyloxymethyl- 4-phenyl-6-chloroquinazoline-3-oxide and the mixture is maintained at 5 to 0 C. for 16-18 hours. The white crystalline precipitate of 7-chloro-2-cyclopropylmethylamino-S-phenyl-3H-1,4benzodiazepine-4-oxide which is obtained melts at 223.5 228 C. To the filtrate an additional 6.00 g. of 2-mesy1oxymethyl-4-phenyl-6-chloroquinazoline-3-oxide is added and a second crop of the benzodiazepine derivative is obtained on completion of the reaction. The second crop is removed by filtration and combined with the first crop. The combined crops are recrystallized from methanol to give purified 7-chloro-2- cyclopropylmethylamine 5 phenyl-'3H-1,4-benzodiazepine-4-oxide which melts at 238239 C.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from' the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patent is:

1. Process for the production of a compound of the formula:

wherein R represents hydrogen; R is a cycloparafiin group having 3 to 4 carbon atoms and R and R reprewherein R is as defined.

'2. A process for the firoduction of 7-chloro 2-cyclo- 'propyIamino-S-phenyl 3H 1,4 benzodiazepine--oxide which comprises reacting 2-mesy1oXymethy1-4-phenyl6- chloro-iquinaz oline-oxide with cyclopropylamine.

3."A processrfor the production of" 7-chkiro 2-cyclo- 7 10 1953),pages666668.

propylmethyl m iii o-5-pheny1-3H 1,4 benzodiazepine-4- oxide which comprises reacting Z-mesyloxymethyllpheny1-6-chloroquinazoline 3 oxide With cyclopropylmethylamine. V V

7 i4 7 '7 References Ciiged by flae Examig er V UNITED STATES PATENTS 2,893,992 ,7/59 Sternbackr 260 23 9 V w OTHER REFERENCES Houben-Weyl, Methoden der Orgnischen Chcroie, vol;

11/ 1 (S'mfigart, 1957), pages 26 and 21 7220. 7

Wagner et al.,, Synthetic Organic Chemisty (New York,

NICHOLAS s. RIZZVQ, Primary Ex alfiiner 7 WALTER A. MQDANCE, Examiner. 

1. PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA: 